Gamma-hydroxybutyric acid or “gamma-hydroxybutyrate” (GHB) is an endogenous compound with hypnotic properties that is found in many human body tissues. GHB is present, for example, in the mammalian brain, the human nervous system and other tissues. The extraordinary range of the pharmacological effects of GHB or its salts has attracted scientific attention for more than three decades. For example, GHB has been found to have tissue-protective effects in animals and man in many different organs including brain, liver, lung, heart, kidney, gut and pancreatic B cells. In brain the highest GHB concentration is found in the hypothalamus and basal ganglia and GHB is postulated to function as a neurotransmitter (Snead and Morley, 1981). The neuropharmacologic effects of GHB include increases in brain dopamine, depression of glucose utilization but not oxygen consumption in the brain, and hypothermia. GHB is converted to succinate and then metabolized via the Krebs cycle. Clinical trials have shown that GHB increases delta sleep and improves the continuity of sleep (Ladinsky et al., 1983; Stock et al., 1973; Laborit, 1973; Lapierre et al., 1990; Yamada et al., 1967; Grove-White and Kelman, 1971; Scharf, 1985).
In healthy human volunteers, low doses (about 30 mg/kg) of GHB monosodium salt (sodium oxybate) promote a normal sequence of NREM and REM sleep lasting about 2-3 hours. These low doses also can induce REM and slow wave sleep and, in contrast to the hypnotics in common use, without the development of tolerance to these sleep-inducing effects in time. In addition, GHB increases total sleep time and REM sleep, and it decreases REM latency (Mamelak et al., 1973; Yamada et al., 1967; Bedard et al., 1989), reduces sleep apnea (Series et al., 1992; Scrima et al., 1987), and improves general anesthesia (Hasenbos and Gielen, 1985).
Studies by R. Broughton and M. Mamelak, Can. J. Neur. Sci., 7, 23 (1980), L. Scrima et al., Sleep, 13, 479 (1990), and M. B. Scharf et al., Am. Fam. Phys., 143 (July 1988) have evaluated the effects of GHB in the treatment of narcolepsy. The results of these studies confirm that GHB treatment substantially reduces the signs and symptoms of narcolepsy (e.g., daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations).
GHB has several clinical applications other than the treatment of sleep disorders. GHB has been reported to reduce alcohol craving, the number of daily drinks consumed, and the symptoms of alcohol withdrawal in patients (Gallimberti et al., 1989; Gallimberti et al., 1992; Gessa et al., 1992). GHB has been used to decrease the symptoms of opiate withdrawal, including both heroin and methadone withdrawal (Gallimberti et al., 1994; Gallimberti et al., 1993). It has analgesic effects that make it suitable as a pain reliever (U.S. Pat. No. 4,393,236). Intravenous administration of GHB has been reported to reduce intracranial pressure in patients (Strong, A. 1984). Also administration of GHB was reported to increase growth hormone levels in patients (Gerra et al., 1994; Oyama et al., 1970). GHB is also an effective therapeutic agent for the treatment of chronic fatigue syndrome and fibromyalgia (Scharf, U.S. Pat. No. 5,990,162).
Unfortunately, the efficacy of GHB is limited by the high doses required to produce a therapeutic effect and by its short duration of action. Thus, a need exists for GHB compositions that can enhance the uptake of the drug, deliver effective therapeutic doses in a time-delayed fashion, and target specific organs.